In Parkinson's disease (PD), degeneration of dopaminergic neurons enervating the striatum causes progressive impairment of motor function. Treatment strategies involve repetitive administration of dopaminergic precursors or agonists. Although very effective, these strategies decline in efficacy in the long- term. The electrical stimulation of subcortical areas of the brain (deep brain stimulation - DBS) is an effective alternative option, which is rather restricted due to its invasiveness and associated risks. Epidural electrical stimulation of the dorsal spinal cord (dorsal column stimulation - DCS) at the upper thoracic level can lead to a dramatic and instantaneous improvement of locomotion in acute and chronic rodent models of PD. This finding has the potential to translate into a minimally invasive, easy to perform, and inexpensive new treatment for PD, available to a broader group of patients. We propose a comprehensive study addressing the mechanisms and efficacy of DCS using different animal models of PD. Our first specific aim is to study the neuronal mechanisms through which DCS achieves its therapeutic effects;we will use Parkinsonian 6-hydroxydopamine striatal lesioned rats implanted with multi-electrode arrays in eight brain areas, including striatum, subthalamic nucleus, globus pallidus, motor and sensory cortices, thalamus, and substantia nigra pars compacta. The effect of DCS on brain activity will be analyzed in terms of neuronal firing rate and oscillatory and synchrony properties of neuronal populations. In the second specific aim, we will evaluate the long term efficacy of DCS. Mice with a genetic mitochondrial dysfunction, which develop progressive dopaminergic neurodegeneration and severe motor impairment through adult life, will be treated daily with DCS from age 8 weeks until the end of their lives (on average about 28 weeks). Open field activity, catalepsy tests and rotating rod tests will be used to evaluate their motor function and compare it to a sham treated group and a levodopa treated group. Other parameters, like lifespan and body weight will also be used as indicators of the long term efficacy of DCS. The third specific aim is to evaluate DCS in two nonhuman primate species, owl monkeys (Aotus trivirgatus) and rhesus macaques (Macaca mulatta), treated with 6-hydroxydopamine. Rhesus monkeys will provide unique information about the effects of DCS on fine motor bimanual reaching/grasping. Owl monkeys will be used to evaluate the effects of DCS and a DCS/L-dopa combination on general mobility and feeding and drinking behavior. Using the analysis of the electrophysiological recordings obtained from both primate species in cortical and subcortical brain areas related to motor control, we will study the neuronal mechanisms of DCS effects. Our laboratory has a unique expertise in multi-electrode electrophysiological recordings in rodents and primates;this expertise, in combination with our competence in dorsal column stimulation, will allow a comprehensive analysis of both the potential mechanisms through which DCS exerts its effects and whether DCS has potential as a viable future treatment for PD patients. PUBLIC HEALTH RELEVANCE: We propose a comprehensive three-stage study to evaluate electrical stimulation of the spinal cord as a treatment for Parkinson's disease. In the first stage, we will perform a mechanistic study using Parkinsonian rats to examine the effect of spinal cord stimulation on the activity of multiple brain areas;in the second stage, mice genetically programmed to develop Parkinsonian symptoms will be used to evaluate the long-term effect of stimulation on motor function;and in the third stage, the concept will be translated to a primate model, where monkeys will be used to test the efficacy of spinal cord stimulation to alleviate Parkinsonian symptoms.